Article

Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors. A Children’s Oncology Group Study

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
Blood (Impact Factor: 10.45). 07/2008; 111(12):5477-85. DOI: 10.1182/blood-2008-01-132837
Source: PubMed

ABSTRACT

Minimal residual disease (MRD) is an important predictor of relapse in acute lymphoblastic leukemia (ALL), but its relationship to other prognostic variables has not been fully assessed. The Children's Oncology Group studied the prognostic impact of MRD measured by flow cytometry in the peripheral blood at day 8, and in end-induction (day 29) and end-consolidation marrows in 2143 children with precursor B-cell ALL (B-ALL). The presence of MRD in day-8 blood and day-29 marrow MRD was associated with shorter event-free survival (EFS) in all risk groups; even patients with 0.01% to 0.1% day-29 MRD had poor outcome compared with patients negative for MRD patients (59% +/- 5% vs 88% +/- 1% 5-year EFS). Presence of good prognostic markers TEL-AML1 or trisomies of chromosomes 4 and 10 still provided additional prognostic information, but not in National Cancer Institute high-risk (NCI HR) patients who were MRD(+). The few patients with detectable MRD at end of consolidation fared especially poorly, with only a 43% plus or minus 7% 5-year EFS. Day-29 marrow MRD was the most important prognostic variable in multi-variate analysis. The 12% of patients with all favorable risk factors, including NCI risk group, genetics, and absence of days 8 and 29 MRD, had a 97% plus or minus 1% 5-year EFS with nonintensive therapy. These studies are registered at www.clinicaltrials.gov as NCT00005585, NCT00005596, and NCT00005603.

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    • "In fact, more than one-third of all relapses occurred in the ΔIKZF1-positive group, with the majority of these (71%) being associated with BCP-other, again strongly suggesting that BCP-other with IKZF1 deletions comprises a specific group characterized by high relapse risk and poor outcome. Minimal residual disease is currently considered to be the most powerful indicator for the outcome of paediatric ALL (Brisco et al, 1993; Cav e et al, 1998; van Dongen et al, 1998; Coustan-Smith et al, 2002; Borowitz et al, 2008; Bj€ orklund et al, 2009). Hence, a major aim of the present study was to ascertain the impact of ΔIKZF1 in the context of MRD, an issue that has been debated (Mullighan et al, 2009; Waanders et al, 2011; Chen et al, 2012; D€ orge et al, 2013; van der Veer et al, 2013; Volejnikova et al, 2013). "
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    ABSTRACT: Paediatric B-cell precursor acute lymphoblastic leukaemias (BCP ALL) with IKZF1 deletions (∆IKZF1) are associated with a poor outcome. However, there are conflicting data as to whether ∆IKZF1 is an independent risk factor if minimal residual disease (MRD) and other copy number alterations also are taken into account. We investigated 334 paediatric BCP ALL, diagnosed 1992-2013 and treated according to Nordic Society for Paediatric Haematology and Oncology ALL protocols, with known IKZF1 status based on either single nucleotide polymorphism array (N = 218) or multiplex ligation-dependent probe amplification (N = 116) analyses. ∆IKZF1, found in 15%, was associated with inferior 10-year probabilities of event-free (60% vs. 83%; P < 0·001) and overall survival (pOS; 73% vs. 89%; P = 0·001). Adjusting for known risk factors, including white blood cell (WBC) count and MRD, ∆IKZF1 was the strongest independent factor for relapse and death. ∆IKZF1 was present in 27% of cases with non-informative cytogenetics ('BCP-other') and a poor 10-year pOS was particularly pronounced in this group (58% vs. 90%; P < 0·001). Importantly, neither MRD nor WBC count predicted events in the ∆IKZF1-positive cases. Co-occurrence of pseudoautosomal region 1 (PAR1) deletions in Xp22.33/Yp11.32 (P2RY8-CRLF2) and ∆IKZF1 increased the risk of relapse (75% vs. 30% for cases with only ∆IKZF1; P = 0·045), indicating that BCP-other ALL with both P2RY8-CRLF2 and ∆IKZF1 constitutes a particularly high-risk group. © 2015 John Wiley & Sons Ltd.
    No preview · Article · May 2015 · British Journal of Haematology
    • "In frontline ALL trials, risk stratification has evolved from looking at prognostic factors at diagnosis to markers of treatment response in vivo, based on evidence that minimal residual disease (MRD) is a poor prognostic factor (Borowitz et al, 2008; Marshall et al, 2013; Sutton et al, 2009; van Dongen et al, 1998). Consequently, patients with high MRD after initial therapy have been given HSCT in first remission in several ALL trials (Flohr et al, 2008; Bruggemann et al, 2010; Marshall et al, 2013). "
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    ABSTRACT: Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment-related mortality of 8%. Leukaemia-free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre-HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre-HSCT (LFS 41%, OS 64%, P < 0·0001) or post-HSCT (LFS 35%, OS 55%, P < 0·0001). Patients with B-other ALL had more relapses (CIR 50%, LFS 41%) than T-ALL and the main precursor-B subtypes including BCR-ABL1, KMT2A (MLL), ETV6-RUNX1 (TEL-AML1) and hyperdiploidy >50. A Cox multivariate regression model for LFS retained both B-other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post-HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post-HSCT therapy.
    No preview · Article · Oct 2014 · British Journal of Haematology
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    • "Moreover, they also showed a strong relationship between day 33 platelet count and MRD measurement that 74% of MRD high-risk patients had low platelet counts and authors proposed this parameter as a surrogate marker of MRD for countries with financial burdens and in situations where MRD cannot be not assessed. Despite these promising results, MRDbased risk stratification remains to be superior to all other clinically relevant risk factors and MRD negativity at the end of induction was found to be the strongest predictor of excellent outcome [16] [17]. "
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    ABSTRACT: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and despite the intense combination chemotherapy, cure rates are less than 90%. Several prognostic parameters, including nonneoplastic hematologic cell counts during induction phase, are suggested to predict outcome in ALL. We analyzed 242 ALL patients treated in our center to investigate individual prognostic parameters and the impact of delays on disease outcome. Age at diagnosis, risk groups, extramedullary involvement, t(9;22), prednisone response, bone marrow response at days 15 and 33, day 15 platelet count, day 33 lymphocyte, monocyte, and platelet counts, treatment delay, sepsis, and omission of day 64 cyclophosphamide were valuable predictors of survival in univariate analysis. However only the age, CNS involvement, omission of cyclophosphamide, and total delay during treatment were associated with survival in multivariate analysis. Omission of second cyclophosphamide dose had no impact on survival of standard risk group patients, but adversely affected the long term survival of medium risk group (MRG) patients. The second dose might be given with the first dose on day 36 to MRG patients to prevent delays. Day 15 and 33 platelet counts are promising predictors of survival in low income countries where assessment of minimal residual disease is difficult, but this data needs further consolidation.
    Full-text · Article · Jun 2014 · Leukemia research
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